U.S. patent application number 10/344608 was filed with the patent office on 2004-02-12 for steroid hormones as transfer agents.
Invention is credited to Hauser, Charlotte.
Application Number | 20040028740 10/344608 |
Document ID | / |
Family ID | 8171921 |
Filed Date | 2004-02-12 |
United States Patent
Application |
20040028740 |
Kind Code |
A1 |
Hauser, Charlotte |
February 12, 2004 |
Steroid hormones as transfer agents
Abstract
The invention relates to compositions containing at least one
stereoid hormone and a non-steroidal pharmaceutically active
compound which compositions are capable of transferring the
pharmaceutically active compounds into cells.
Inventors: |
Hauser, Charlotte; (Munich,
DE) |
Correspondence
Address: |
David J Kulik
Wiley Rein & Fielding
1776 K Street, NW
Washington
DC
20006
US
|
Family ID: |
8171921 |
Appl. No.: |
10/344608 |
Filed: |
September 11, 2003 |
PCT Filed: |
August 15, 2001 |
PCT NO: |
PCT/EP01/09409 |
Current U.S.
Class: |
424/486 |
Current CPC
Class: |
A61K 47/28 20130101;
A61K 9/145 20130101; A61K 45/06 20130101 |
Class at
Publication: |
424/486 |
International
Class: |
A61K 009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Aug 15, 2000 |
EP |
00202858.7 |
Claims
1. A pharmaceutical composition comprising at least one micronized
steroid hormone and a non-steroidal pharmaceutically active
compound selected from low molecular pharmaceutically active
compounds with the exception of steroid hormones and
pharmaceutically active polymeric structures with the exception of
polymeric structures essentially comprised of nucleic acids,
wherein the molar ratio of steroid hormone to non-steroidal
pharmaceutically active compound is at least 50:1.
2. The composition of claim 1, wherein the steroid hormone is
selected from estrogen, testosterone, glucocorticoid, androgen,
thyroid hormone and progesterone and derivatives thereof, and
preferably is progesterone.
3. The composition of claim 1 or 2, wherein the steroid hormone is
a natural micronized steroid hormone.
4. The composition of claims 1 to 3, wherein the non-steroidal
pharmaceutically active compound is a low molecular weight compound
or a polymeric compound substantially comprised of amino acid
residues.
5. The composition of claims 1 to 4 wherein the molar ratio of
steroid hormone to non-steroidal pharmaceutically active compound
is at least 250:1, preferably at least 1000:1, and more preferably
at least 10000:1.
6. The composition of claims 1 to 5 further comprising a lipophilic
matrix.
7. The composition of claims 1 to 6, wherein the pharmaceutically
active compound is encapsulated in the steroid hormone and/or
wherein the composition is suitable for transferring
pharmaceutically active compounds into cells.
8. Use of a steroid hormone for preparing a medicament for
transferring a non-steroidal pharmaceutically active compound as
defined in claim 1 to an organism, wherein in the medicament the
molar ratio of steroid hormone to non-steroidal pharmaceutically
active compound is at least 50:1.
9. The use of claim 8, wherein the steroid hormone is a natural
micronized steroid hormone, preferably natural micronized
progesterone.
10. The use of claim 9, wherein the natural micronized steroid
hormone is solubilized in a lipophilic matrix.
11. A method for transferring a non-steroidal pharmaceutically
active compound as defined in claim 1 to an organism or to a
cellular system, which method comprises administering the active
compound to the organism or to the cellular system in admixture
with a steroid hormone, wherein the molar ratio of steroid hormone
to non-steroidal pharmaceutically active compound is at least
50:1.
12. The method of claim 11 wherein the pharmaceutically active
compound is encapsulated in the steroid hormone.
Description
OBJECT OF THE INVENTION
[0001] The invention relates to compositions containing at least
one steroid hormone and a non-steroidal pharmaceutically active
compound which compositions are capable of transferring the
pharmaceutically active compounds into cells.
SUMMARY OF THE RELATED ART
[0002] The transfer of pharmaceutically active compounds into cells
is a goal for pharmaceutical research. Not only for gene therapy
which involves the transfer of recombinant genes or transgenes into
somatic cells to replace proteins with a genetic defect or to
interfere with the pathological process of an illness, but also for
transferring non-DNA compounds a safe and easy system is still
wanted. Currently the transfer of non-DNA compounds into cells is
achieved via oral, nasal or mucosal administration, subcutaneous or
i.v. application, or the like. However, in these methods the
compounds have to be adopted to pass membrane barriers which
consequently imposes severe limitations on the structures of the
compounds to be administered. With regard to gene therapeutic
methods it is referred to the methods summarized in PCT/EP00/01368
(filed Mar. 3, 2000).
[0003] On the other hand, the classical model of the action of
hormones is based on the concept of binding interaction of the
hormone to an intracellular receptor, located in the cytoplasm or
the nucleus (Evans, R., Science, Vol. 240, 889, 1988). These
intracellular receptors remain latent until exposed to their target
hormone. When so exposed, the hormone receptor changes its
conformation after the hormone is bound and translocates in the
activated form into the cell nucleus where it binds as a dimer to
hormone responsive elements in the promoter region of
hormone-regulated genes (Beato, M., Cell, Vol. 56, 335, 1989;
O'Malley, B., et al., Biol. Reprod., Vol. 46, 163, 1992). The
hormone responsive elements are enhancer elements usually located
in the 5' flanking region of the specific hormone-induced gene,
i.e., are functionally linked to the specific hormone induced gene.
DNA constructs comprising a hormone responsive element and a
nucleic acid sequence encoding a protein of interest are disclosed
in U.S. Pat. Nos. 5,688,677 and 5,580,722 and are taught to be
suitable for expression of the protein of interest.
[0004] An example of such intracellular receptors is the steroid
receptor. Steroid . receptors belong to a superfamily of
ligand-dependent transcription factors characterized by a unique
molecular structure. The centrally located highly conserved
DNA-binding domain defines this superfamily. The second important
and relatively invariant region is the COOH-terminal ligand-binding
domain. An example of such a receptor is the progesterone receptor
mediated by the steroid progesterone. At the progesterone receptor,
progesterone acts as a natural agonist whereas it displays potent
antimineralocorticoid properties both at the molecular and the
systemic level. Besides classical effects on the uterus,
antiepileptic, anxiolytic, hypnotic and anesthetic properties have
been attributed to progesterone according to numerous studies.
Specifically, U.S. Pat. Nos. 4,196,188 and 5,140,021 disclose
pharmaceutical compositions comprising finely ground progesterone
particles having a particle size of less than 15 and 10 .mu.m,
respectively and being suspended in an oil vehicle (so-called
"micronized progesterone"), said compositions being suitable as
contraceptive and for the treatment of premenstrual syndrome;
[0005] GB 1535531 discloses antiallergics and antiasthmatics
comprising mixtures of micronized antiallergically active steroids
(such as 17-esters of .beta.-methasone and of prednisolone) and
micronized thymol derivatives);
[0006] GB 951767 discloses pharmaceutical compositions comprising
mixtures of hydrocortisone derivatives and decongestants;
[0007] U.S. Pat. No. 3,800,038 discloses pharmaceutical
preparations comprising a steroid hormone in a steroidal lipid
carrier, said preparations optionally containing further
pharmaceutically active compounds such as antimicrobial agents;
and
[0008] WO 98/42185 discloses a method for generating a mouse model
for human endometriosis, which method comprises adding a micronized
exogenous estrogen source and an antibiotic to a severely
compromised immunodeficient female mouse.
[0009] However, the ratio of steroid hormone to additional
pharmaceutical compound in the above compositions or methods is not
given or the steroid hormone and additional pharmaceutical compound
are utilized in approximately equal amounts.
[0010] Recently it was found that steroid hormones, e.g., such as
the micronized progesterone, are very effective mediators for the
transfer of nucleic acid constructs through the cell membranes into
a cell (PCT/EP00/01368). It was now found that such steroid
hormones especially if used in large excess--are also effective
mediators of (non-nucleic acid) pharmaceutically active compounds
for the transport of said compounds through the cell membranes into
a cell.
BRIEF DESCRIPTION OF THE INVENTION
[0011] The present invention thus provides
[0012] (1) a pharmaceutical composition comprising at least one
steroid hormone and a non-steroidal pharmaceutically active
compound, preferably the molar ratio of steroid hormone to
non-steroidal pharmaceutically active compound being at least
50:1;
[0013] (2) a preferred embodiment of (1) above, wherein the steroid
hormone is a natural micronized steroid hormone;
[0014] (3) use of steroid hormone for preparing an agent for
transferring a non-steroidal pharmaceutically active compound into
cells; and
[0015] (4) a method for transferring a non-steroidal
pharmaceutically active compound to an organism or to a cellular
system, which method comprises administering the active compound to
the organism or to the cellular system in admixture with a steroid
hormone.
DETAILED DESCRIPTION OF THE INVENTION
[0016] "Non-steroidal pharmaceutically active compounds"
(hereinafter also shortly referred to as "pharmaceutical
compounds") refers to pharmaceutically active compounds which are
low molecular pharmaceutically active compounds (except steroid
hormones) and polymeric structures with the exception of polymeric
structures essentially comprised of nucleic acids such as nucleic
acid constructs.
[0017] In the above "nucleic acid" means DNA, cDNA, mRNA, tRNA,
rRNA. The nucleic acid may be linear or circular, double-stranded
or single-stranded, and "nucleic acid construct" refers to a
composite of nucleic acid elements in relation to one another.
"Polymeric structures" according to the present invention include
polymers essentially comprised of amino acid residues (e.g.,
peptides, proteins -and other proteinacious structures),
polyhydroxy compounds (such as carbohydrates, glycoproteins etc.)
polyamines and the like.
[0018] "Organism" refers to a multicellular living entity including
vertebrates such as mammals (especially humans, cattle, rodents,
dogs) and invertebrates.
[0019] "Cellular system" includes cell cultures, e.g., primary cell
cultures (especially those suitable for reimplantation), stem
cells, blood cells, tissue samples and whole organs and
immortalized cell cultures.
[0020] "Therapeutically effective dose" within the ambit of the
present invention refers to a dose effective for treatment or
prophylaxis, or a dose that is predictable to be effective for
treatment or prophylaxis by. extrapolating from in vitro or in vivo
data. The determination of a therapeutically effective dose is
within the purview of one skilled in the art.
[0021] As stated above, an object of the present invention is to
provide a new and improved delivery system.
[0022] The steroid hormone in the composition of embodiment(s) (1)
and (2) and in the medicament of the embodiment (3) include
synthetic and natural steroid hormones, such as estrogen,
testosterone, glucocorticoid, androgen, thyroid hormone, and
progesterone or derivatives thereof. These are widely available.
Progesterone is most preferred. For example, natural micronized
progesterone is the preferred progesterone from which has been
marketed in France since 1980 under the trademark of
UTROGESTAN.RTM. and is still available in Germany under the
trademark UTROGEST.RTM.. Its properties are similar to the
endogenous progesterone, in particular, it has antiestrogen,
gestagen, slightly antiandrogen and antimineralocorticoid
properties. The natural micronized progesterone in said marketed
products is dispersed in a matrix as described herein below.
[0023] The above micronized progesterone has advantages that make
it a suitable carrier for genes or nucleic acid constructs to
target cells. Specifically, the synergistic effect of the double
process of micronization and suspension a lipophilic matrix (see
below), especially in long-chain fatty acids residues of an oil
results in increasing progesterone absorption. It has been
demonstrated that after oral administration of 100 mg of
UTROGESTAN.RTM., peak plasma progesterone levels were obtained
after 1-4 hours in most cases (Padwick, M. L., et al., Fertil.
Steril., Vol. 46, 402, 1986). Later on, the levels declined
substantially, although they were still elevated at 12 hours. Even
at 84 hours the levels were slightly higher than baseline. A
kinetic study confirmed earlier work by demonstrating the
bioavailability of oral micronized progesterone. It was shown that
a peak effect at 2 hours was followed by rapid decrease in plasma
progesterone level (Simon, J. A., et al., Fertil., Steril, Vol.,
60, 26, 1993).
[0024] A further advantage of using progesterone as a carrier is
the low level of disadvantageous side effects. Orally administered
progesterone adversely affects neither plasma lipids (Jensen, J. et
al., Am. J. Obstet. Gynecol., Vol. 156, 66, 1987) nor carbohydrate
metabolism (Mosnier-Pudar, H. et al., Arch. Mal. Coeur, Vol 84,
1111, 1991). Further, progesterone does not affect liver enzymes
(ASAT, ALAT, AFOS), sex-hormone binding-globulin (SHBG) synthesis
or HDL-cholesterol levels at daily doses of 200 mg and 300 mg.
Although the plasma levels of deoxycorticosterone may increase
substantially during UTROGESTAN.RTM. treatment, there are strong
indications that the mineralocorticoid effects of this progesterone
metabolite are completely counteracted by the
anti-mineralocorticoid effects of progesterone itself. This is
apparent from a comparative study (Corvol, P., et al., In:
Progesterone and progestins. Raven Press, New York, 179, 1983) in
which oral UTROGESTAN.RTM. was capable of antagonizing the
mineralocorticoid effects of 9-.alpha.-fluorohydrocortisone.
[0025] In the composition of embodiment (1) and (2) and in the
medicament of embodiment (3) of the invention the molar ratio of
hormone to pharmaceutical compound is at least 50:1, preferably at
least 250:1, more preferably at least 1000:1, and most preferably
at least 10000:1. It has been found that below a ratio of 50:1, the
transfer of the pharmaceutical compound into the cell is less
effective.
[0026] The skilled artisan will appreciate that the composition of
embodiments (1) and (2) and the medicament of embodiment (3) may
contain other components capable of assisting in introducing the
nucleic acid into a cell for the purpose of gene therapy (e.g., the
matrix compounds mentioned hereinbefore). Specifically, the
composition and the medicament, especially the hormone component
thereof, may contain the following matrix compounds: glucose and
related compounds (such as D-sorbitol, D-mannitol); solubilizing
adjuvants (such as alcohols, e.g., ethanol); polyhydric compounds
such as glycerine, polyethylene glycol and polypropylene glycol;
nonionic surface active compounds, ionic surface active compounds
such as lecithin; oily compounds such as sesame oil, peanut oil
soybean oil, corn oil, etc.; starches and their derivatives such as
cyclodextrines and hydroxyalkylated starches; stabilizers such as
human serum albumin, preservatives such as benzyl alcohol and
phenol; and the like. The preferred matrix contains
B-cyclodextrine, glycerine, lecithin and/or corn oil. In case of
micronized steroid hormones such as micronized progesterone the
micronized particles are suspended in an oil vehicle, preferably an
oil vehicle which is high in glycerides of polyunsaturated fatty
acids such as corn oil, sunflower oil and soybean oil (see U.S.
Pat. No. 5,140,021; the disclosure of which is incorporated herein
by reference). Preferably, the oil:micronized steroid hormone ratio
does not exceed 2.5 ml oil per gram steroid hormone.
[0027] For example, the pharmaceutical composition of steroid
hormone and pharmaceutical compound of the invention may be
provided orally to humans or animals as a gelatin capsule.
Progesterone therein (preferably in micronized form) could be
present in a concentration of 50 to 1000 mg, preferably 200 to 300
mg dissolved in a 35% or 40% .beta.-cyclodextrin solution or in
corn oil or gycerol with peanut oil together with lecithin.
[0028] Alternatively, when--due to the selection of appropriate
matrix components--the pharmaceutical composition is in a pasty,
gel-like form, it may be provided topically.
[0029] The composition of embodiment (1) of the invention can be
prepared by admixing the pharmaceutical compound with the hormone.
Preferably, an aqueous solution of pharmaceutical compound (if the
compound is soluble in such aqueous systems) is added to the oily
suspension containing the hormone at ambient temperature under
stirring.
[0030] The dose of non-steroidal compound is dependent on the
condition to be treated, the characteristics of the patient, and
the result sought to be achieved. Determining dosage is within the
realm of the skilled artisan.
[0031] The pharmaceutical composition and the medicament of the
present invention may be administered orally, rectally,
intravenously, intramuscularly, subcutaneously, topically or
through mucosa (including buccal, nasal spray). Oral administration
(of a micronized hormone dispersion) is preferred. Delivery may be
systemic or directed at certain tissue.
[0032] Embodiments (3) and (4) of the invention pertain to the use
of a steroid hormone for preparing an agent for transferring a
non-steroidal pharmaceutically active compound to an organism and
to a method for transferring a non steroidal pharmaceutically
active compound to an organism or to a cellular system, which
comprises administering the active compound to the organism or to a
cell system. In a preferred embodiment the active compound is
encapsulated in the steroid hormone. Suitable steroid hormones are
enumerated above. The preferred steroid hormone in said embodiments
of the invention is a natural micronized steroid hormone, in
particular a natural micronized progesterone. In a preferred
embodiment, the micronized hormone is solubilized/dispersed in a
lipophilic matrix as set forth above. The dose and mode of
administration is within the ambit of a person skilled in the
art.
[0033] Preferred mixtures of steroid hormones and pharmaceutically
active compounds according to the present invention are the amount
of progesterone contained in a capsule UTROGEST.RTM. (viz. 100 mg
progesterone) with less than 4 .mu.mol, preferably less than 0.5
.mu.mol, more preferably less than 0.1 .mu.mol pharmaceutically
active compound selected from, but not limited to, enzymes, enzyme
inhibitors, growth hormones, cytokines, cytostatics, blood clotting
factors and immune modulators.
* * * * *